Prosthetic devices having enhanced osteogenic properties

Abstract

A prosthetic device comprising a prosthesis coated with substantially pure osteogenic protein is disclosed. A method for biologically fixing prosthetic devices in vivo is also disclosed. In this method, a prosthesis is implanted in an individual in contact with a substantially pure osteogenic protein, enhancing the strength of the bond between the prosthesis and the existing bone at the joining site.

What is claimed is: 
     
       1. A method for promoting in vivo osseointegration of an implantable, prosthetic device, the method comprising the steps of: providing on a surface of the prosthetic device substantially pure osteogenic protein, and   implanting the device in a mammal at a site wherein bone tissue and said surface are maintained at least partially in contact for a time sufficient to permit enhanced bone tissue growth between said tissue and said device; wherein said osteogenic protein is a basic protein comprising a pair of polypeptide chains, one of said polypeptide chains comprising an amino acid sequence sharing greater than 60% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS) such that said pair of polypeptide chains, when disulfide bonded to produce a dimeric species, has a conformation capable of inducing endochondral bone formation when disposed in a matrix and implanted in a mammal.   
     
     
       2. In the method of repairing the skeletal system of a mammal comprising surgically implanting in contact with bone tissue a prosthetic device, and permitting the device and the bone tissue to integrate to form a weight bearing skeletal component, the improvement comprising: providing substantially pure osteogenic protein on a surface of said device prior to its implantation thereby to promote enhanced bone tissue growth into said device and to improve the tensile strength of the junction between the bone and said device; wherein said protein is an osteogenically active protein, characterized in that the protein is a basic protein comprising a pair of polypeptide chains, one of said polypeptide chains comprising an amino acid sequence sharing greater than 60% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS) such that said pair of polypeptide chains, when disulfide bonded to produce a dimeric species, has a conformation capable of inducing endochondral bone formation when disposed in a matrix and implanted in a mammal.   
     
     
       3. The method of claim 1 or 2 wherein said surface of said prosthetic device further comprises hydroxylapatite, collagen, homopolymers or copolymers of glycolic acid, lactic acid or butyric acid and derivatives thereof, tricalcium phosphate or other calcium phosphate, metal oxides or combinations thereof. 
     
     
       4. The method of claims 1 or 2 wherein the prosthetic device comprises a porous, metallic material. 
     
     
       5. The method of claim 1 or 2 wherein said dimeric osteogenic protein is produced by recombinant DNA in a host cell and is isolated therefrom. 
     
     
       6. The method of claim 1 or 2 wherein the osteogenic protein is an osteogenically active dimeric protein expressed from recombinant DNA in a host cell, further characterized in that the protein comprises a pair of oxidized subunits disulfide bonded to produce a dimeric species, one of said subunits having an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding OPS (residues 335 to 431 of Seq. ID No. 1) under stringent hybridization conditions, such that the disulfide bonded dimeric species comprising said subunit has a conformation capable of inducing endochondral bone formation in a mammal when disposed on the surface of said device. 
     
     
       7. The method of claim 5 wherein said dimeric osteogenic protein is unglycosylated. 
     
     
       8. The method of claim 1 or 2 wherein each said polypeptide chain of said protein comprises an amino acid sequence sharing greater than 65% identity with an amino acid sequence comprising OPS. 
     
     
       9. The method of claim 8 wherein the amino acid sequence of one of said polypeptide chains comprises the amino acid sequence defined by residues 335-431 of Seq. ID No. 1 (OPS). 
     
     
       10. The method of claim 8 wherein both said polypeptide chains comprise the amino acid sequence defined by residues 335-431 of Seq. ID No. 1 (OPS.) 
     
     
       11. The method of claim 10 wherein both said polypeptide chains comprise the amino acid sequence of residues 318-431 of Seq. ID No. 1 (OP1-16 Val.) 
     
     
       12. An improved prosthetic device for repairing mammalian skeletal defects, injuries, or anomalies comprising a rigid prosthetic implant having a porous or non-porous surface region for implantation adjacent bone tissue, wherein the improvement comprises: substantially pure osteogenically active osteogenic protein disposed on said surface region in an amount sufficient to promote enhanced bone tissue growth into said surface; wherein said protein is an osteogenically active protein, characterized in that the protein is a basic protein comprising a pair of polypeptide chains, one of said polypeptide chains comprising an amino acid sequence sharing greater than 60% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS) such that said pair of polypeptide chains, when disulfide bonded to produce a dimeric species, has a conformation capable of inducing endochondral bone formation when disposed in a matrix and implanted in a mammal.   
     
     
       13. The device of claim 12 wherein said surface of said prosthetic device further comprises hydroxylapatite. 
     
     
       14. The device of claim 12 wherein said dimeric osteogenic protein is produced by recombinant DNA in a host cell and is isolated therefrom. 
     
     
       15. The device of claim 14 wherein said dimeric osteogenic protein is unglycosylated. 
     
     
       16. The device of claim 12 wherein one of said polypeptide chains comprises an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding OPS (residues 335-431 of Seq. ID No. 1), such that the disulfide bonded dimeric species comprising said polypeptide chain has a conformation capable of inducing endochondral bone formation in a mammal when disposed on the surface of said device. 
     
     
       17. The device of claim 12 wherein each of said polypeptide chains comprises an amino acid sequence sharing greater than 65% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS). 
     
     
       18. The device of claim 17 wherein one of said polypeptide chains of said protein comprises residues 335-431 of Seq. ID No. 1 (OPS). 
     
     
       19. The device of claim 17 wherein both said polypeptide chains comprise the amino acid sequence defined by residues 335-431 of Seq. ID No. 1 (OPS). 
     
     
       20. The device of claim 19 wherein both said polypeptide chains comprise the amino acid sequence defined by residues 318-431 of Seq. ID No. 1 (OP1-16 Val.) 
     
     
       21. The device of claim 12 wherein the prosthesis comprises a porous metallic material. 
     
     
       22. The device of claim 12 wherein the prosthesis comprises a contoured implantable portion for insertion into an orifice having plural indentations transverse to its longitudinal axis. 
     
     
       23. The device of claim 22 comprising a dental implant. 
     
     
       24. A method for promoting in vivo osseointegration of a prosthetic device into an orifice of a bone, comprising the steps of: providing a prosthetic device having a contoured implantable portion for insertion into said orifice, said contoured portion having plural indentations transverse to its longitudinal axis, and   implanting into the orifice the contoured portion of the prosthetic device and a bond growth composition comprising a substantially pure osteogenic protein combined with a matrix material which induces bone growth in said indentations, osseointegration between the bone and the prosthetic device, and osseointegration of new bone induced by said composition and said bone; wherein said protein is an osteogenically active protein, characterized in that the protein is a basic protein comprising a pair of polypeptide chains, one of said polypeptide chains comprising an amino acid sequence sharing greater than 60% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS) such that said pair of polypeptide chains, when disulfide bonded to produce a dimeric species, has a conformation capable of inducing endochondral bone formation when disposed in a matrix and implanted in a mammal.   
     
     
       25. The method of claim 24 wherein the contoured portion comprises a porous metallic material. 
     
     
       26. The method of claim 25 wherein the osteogenic protein enhances bone ingrowth into said pores. 
     
     
       27. The device of claim 24 or 29 wherein said protein is produced by recombinant DNA in a host and is isolated therefrom. 
     
     
       28. The device of claim 27 wherein said protein is unglycosylated. 
     
     
       29. A device for promoting in vivo osseointegration of a prosthesis into an orifice of a bone, comprising a rigid prosthetic implant having a contoured portion for insertion into said orifice, said contoured portion having plural indentations transverse to its longitudinal axis, and   a bone growth composition comprising a substantially pure osteogenic protein combined with a matrix material which induces bone growth in said indentations, osseointegration between the bone and the prosthetic implant and osseointegration of new bone induced by said composition and said bone; wherein said protein is an osteogenically active protein characterized in that the protein is a basic, dimeric protein and comprises a pair of polypeptide chains, one of said polypeptide chains having an amino acid sequence sharing greater than 60% identity with the amino acid sequence defined by residues 335 to 431 of Seq. ID No. 1 (OPS) such that said pair of polypeptide chains, when disulfide bonded to produce a dimeric species, has a conformation capable of inducing endochondral bone formation in association with said contoured portion of said prosthesis when implanted in a mammal.   
     
     
       30. The device of claim 29 wherein the contoured portion comprises a porous metallic material. 
     
     
       31. The device of claim 30 wherein the osteogenic protein enhances bone ingrowth into said pores. 
     
     
       32. The device of claim 29 wherein said matrix material is selected from the group consisting of hydroxylapatite, collagen, polymers or copolymers of glycolic acid, lactic acid or butyric acid, tricalcium phosphate or other calcium phosphates, metal oxides, demineralized guanidine extracted bone and combinations thereof. 
     
     
       33. The device of claim 29 comprising a dental implant.